FXR is a member of the nuclear hormone receptor superfamily, and is mainly expressed in the liver, kidneys and intestines (Seol et al. Mol. Endocrinol (1995), 9:72-85; Forman Cell (1995), 81:687-693). It functions as a heterodimer with the RXR, and regulates gene transcription by binding to the response elements of the target gene promoter. The FXR-RXR heterodimer binds with highest affinity to an inverted repeat-1 (IR-1) response element, wherein consensus receptor-binding hexamers are separated by a nucleotide. FXR is activated by bile acids (cholesterol metabolism end products) (Makishima et al., Science (1999), 284:1362-1365; Parks et al., Science (1999), 284:1365-1368; Wang et al., Mol. Cell. (1999), 3:543-553), and the bile acid is used to inhibit cholesterol catabolism. (Urizar et al., (2000) J. Biol. Chem. 275:39313-393170).
FXR is a critical regulator of cholesterol homeostasis, triglyceride synthesis and adipogenesis (Crawley, Expert Opinion Ther. Patents (2010), 20:1047-1057). In addition to target for treating dyslipidemia, obesity, vitamin D-related diseases, intestinal diseases, drug-induced side effects as well as hepatitis (Crawley, Expert Opinion Ther. Patents (2010), 20:1047-1057), FXR is also the target of hepatic and gall disease, chronic hepatitis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cholestasis, liver fibrosis, cirrhosis of liver, hepatitis B, metabolic diseases, lipid metabolism disorders, carbohydrate metabolic diseases, cardiovascular and metabolic diseases, atherosclerosis, type II diabetes and diabetic complications (Frank G. Schaap et al., Journal of Medicinal Chemistry, (2005), 48:5383-5402).
Small molecule compounds which act as FXR modulators have been disclosed in the following patents: WO 2000/037077, WO 2003/015771, WO 2004/048349, WO 2007/076260, WO 2007/092751, WO 2007/140174, WO 2007/140183, WO 2008/051942, WO 2008/157270, WO 2009/005998, WO 2009/012125, WO 2009/149795, WO 2008/025539, WO 2008/025540, WO 2012/087520, WO 2012/087521, WO 2012/087519, WO2013/007387 and WO 2015/036442. R. C. Buijsman et al. also reviewed more-small molecule modulators of FXR (R. C. Buijsman et al., Curr. Med. Chem. 2005, 12, 1017-1075).
Although the development of FXR modulators has a certain progress, the development space is still enormous.